1. Field of the Invention
The present invention relates generally to medical devices and methods. More particularly, the present invention relates to methods and apparatus for inhibiting neointimal hyperplasia in arteries following angioplasty, stenting, or other intravascular procedures for treating atherosclerotic disease.
A number of percutaneous intravascular procedures have been developed for treating atherosclerotic disease in a patient's vasculature. The most successful of these treatments is percutaneous transluminal angioplasty (PTA) which employs a catheter having an expansible distal end, usually in the form of an inflatable balloon, to dilate a stenotic region in the vasculature to restore adequate blood flow beyond the stenosis. Other procedures for opening stenotic regions include directional atherectomy, rotational atherectomy, laser angioplasty, stents and the like. While these procedures, particularly PTA followed by stenting, have gained wide acceptance, they continue to suffer from the subsequent occurrence of restenosis.
Restenosis refers to the re-narrowing of an artery within weeks or months following an initially successful angioplasty or other primary treatment. Restenosis afflicts up to 50% of all angioplasty patients and results at least in part from vascular smooth muscle cell proliferation in response to the injury caused by the primary treatment, generally referred to as "neointimal hyperplasia." Blood vessels in which significant restenosis occurs will require further treatment.
A number of strategies have been proposed to reduce restenosis. Such strategies include prolonged balloon inflation, treatment of the blood vessel with a heated balloon, treatment of the blood vessel with ionizing radiation, the administration of anti-thrombotic drugs following the primary treatment, stenting of the region following the primary treatment, and the like. While enjoying different levels of success, no one of these procedures has proven to be entirely successful in treating all occurrences of restenosis.
Of particular interest to the present invention, the application of ionizing radiation from radioisotopes following angioplasty has shown great promise for the inhibition of hyperplasia. Despite its great promise, the use of intravascular radiation suffers from a number of proven and suspected deficiencies. Such ionizing radiation treatments do not appear to promote healing of the endothelial layer which forms over the neointimal layer, particularly over stented regions of a treated artery. The radiation may also be harmful to the medial region of the arterial wall, subjecting the patient to long-term risk. On a practical level, the need to handle and dispose of radioisotopes is problematic and presents some risk to both the patient and the individuals treating the patient. While the use of isotopes having a very short half-life reduces these problems somewhat, the fabrication and inventory maintenance of catheters and devices employing such isotopes is difficult because the very short shelf-life. It will be appreciated that the window of opportunity for using isotopes having a very short half-life is quite limited.
The use of ultrasound energy for treating restenosis on a blood vessel has been proposed in U.S. Pat. No. 5,836,896. In particular, that patent teaches that high amounts of ultrasonic energy can be delivered to a blood vessel in order to reduce the viability, migration, and adhesion of smooth muscle cells. The ultrasonic energy is delivered under conditions which cause cavitation within the smooth muscle cells. The preferred operational parameters are low frequency (15 kHz to 250 kHz) and high energy capable of causing the intended cavitation. In a particular example, use of a longitudinal vibration transmission wire to first recanalize an artery and subsequently radiate the vascular intima to inhibit smooth muscle cell migration, viability, and adherence is described. While positive results are reported, there are no controls to confirm whether the post-recanalization therapy was responsible for the observed patency.
For these reasons, it would be desirable to provide alternative methods and apparatus for the treatment of intimal hyperplasia in arteries following angioplasty, stenting, and other recanalization treatments. It would be particularly desirable to provide methods and apparatus for the application of vibrational energy to the arterial wall, where the energy would at least partly inhibit excessive cell proliferation of vascular smooth muscle cells in the neointimal layer which forms following a primary treatment and which can result in hyperplasia and subsequent restenosis of the blood vessel. It would be even more desirable if the energy source were generated in situ within the blood vessel and were of a type which may be readily turned on and turned off without exposing the patient and treating personnel to significant risk. The apparatus intended for performing the method should be suitable for vascular introduction, preferably via percutaneous intravascular access. In addition, it would be desirable to provide methods for inhibiting the hyper-proliferation of vascular smooth muscle cells in the neointimal layer following arterial injury without substantially diminishing the viability or migration capability of the cells. It would be still further desirable to provide for ultrasonic and other vibrational therapy for the inhibition of neointimal hyperplasia without inducing substantial cavitation or creating substantial heating in the arterial wall being treated. Such treatments would desirably promote healing and re-endothelialization of the arterial wall. At least some of these objectives will be met by the invention described hereinafter.
2. Description of the Background Art
Intravascular inhibition of hyperplasia by exposure to radioisotopes is described in a number of patents and publications, including U.S. Pat. Nos. 5,616,114; 5,302,168; 5,199,939; and 5,059,166. The therapeutic application of ultrasonic energy is described in a number of patents and publications including U.S. Pat. Nos. 5,362,309; 5,318,014; 5,315,998, WO 98/48711; and others.
The application of intravascular ultrasound for inhibiting restenosis by decreasing the migration, viability, and adhesion of vascular smooth muscle cells via a cavitation mechanism is suggested in U.S. Pat. No. 5,836,896. Vascular smooth muscle cell migration, however, has been shown not to contribute significantly to neointimal thickening after arterial injury. See, Bendeck et al. (1996) Circ. Res. 78:38-43. Vascular smooth muscle cell, migration, and adhesion have been shown to decrease in cell culture in response to ultrasonically induced cavitation. Alter et al. (1998) Ultrasound in Medicine 24:711-721. See also Rosenchein et al. (1990) JACC 15:711-717 and Siegel et al. (1991) J. Invasive Cardiol. 3:135 which describe thrombolysis via the cavitation mechanism.
A high frequency ultrasonic catheter intended for tissue ablation which employs an air-backed transducer is described in He et al. (1995) Eur. Heart J. 16:961-966. Cell lysis of mammalian cell lines maintained in vitro is described in Kaufman et al. (1977) Ultrasound Med. Biol. 3:21-25. Catheters suitable for performing at least some methods according to the present invention are described in co-pending application Ser. Nos. 08/565,575; 08/566,740; 08/566,739; 08/708,589; 08/867,007, and 09/223,225 and assigned to the assignee of the present invention, the full disclosures of which are incorporated herein by reference.